CRISPR mediated overexpression of cocaine hydrolyzing enzyme in mouse skin patch protects against lethal overdose

By Rajaneesh K Gopinath

A promising new approach developed by a team of researchers at the University of Chicago has raised fresh hopes in treating cocaine addiction and overdoses in the near future. The breakthrough is an outcome of a collaborative endeavor between the labs of Ming Xu, Professor of Anesthesia & Critical Care, and Xiaoyang Wu, Assistant professor in the Ben May Department for Cancer Research. The results of this study are published in the September 17th issue of Nature Biomedical Engineering journal [1].

Xiaoyang Wu’s lab had made the headlines last year when they successfully employed CRISPR gene editing to manufacture insulin in skin grafts of diabetic mice [2]. This time around, they applied the same technique to overexpress an enhanced form of human butyrylcholinesterase (BChE) in mouse skin epidermal stem cells. BChE is a naturally occurring enzyme found in humans that hydrolyses cocaine but it has a very short half-life. The team used E30-6, which has a more specific catalytic activity in cocaine conversion thereby enhancing its hydrolyzing capacity to up to 4,400 times [3].

Using the CRISPR technology, the gene was inserted into the primary epidermal basal progenitor/stem cells collected from newborn mice. The cells were initially seeded onto circular, 1-centimeter-across patches of scaffolding to make organoids, which were then transplanted in to the immunocompetent donor mice addicted to cocaine. The engineered skin grafts exhibited normal epidermal stratification, proliferation and cell death. It was observed that the robust expression of human BChE protected the mice from cocaine-seeking and cocaine-induced relapse and also prevented its death against doses that are otherwise lethal.

One of the major obstacles in treating cocaine addiction is that, despite long periods of rehabilitation and recovery, victims could suffer relapses due to compulsive drug seeking. That explains the non-availability of an FDA approved drug therapy till date to counter this menace. According to the National Survey on Drug Use and Health (NSDUH) conducted in 2014, an annual estimate of approximately 913,000 Americans met the criteria of mental disorder due to cocaine abuse [4]. The authors are confident that the genome-edited skin stem cells can be used to deliver an active cocaine hydrolase long term in vivo and this promises to be an effective therapeutic option to treat cocaine abusers in future [5].

References
https://www.nature.com/articles/s41551-018-0293-z/
https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(17)30274-6
https://www.nature.com/articles/ncomms4457?origin=ppub
https://www.drugabuse.gov/publications/research-reports/cocaine/what-scope-cocaine-use-in-united-states
https://www.sciencedaily.com/releases/2018/09/180917111609.htm

Author

Rajaneesh K. Gopinath